Our overall objective is to interrelate the time course of systolic and diastolic load to the myocardium with the compensatory reflex- hemodynamic changes and the structural and ultrastructural alterations in lower animals as well as in man. When feasible the hemodynamics will be determined in the conscious dog; an endeavor will be directed to combining the thermodilution technique for the determination of end diastolic colume, systolic volume, and stroke volume with the balloon technique for obstructing the pulmonary artery in order to study the hemodynamic changes of a pressure overload. The following will be studied: 1) the role of the autonomic nervous system in the hemodynamic reflex produced by pulmonary arterial obstruction and distention with special reference to pulmonary arteriolar constriction and respiratory augmentation. 2) the compliance of the acute and chronic pressure overloaded ventricle in relation to the influence of the pericardium, and the autonomic nervous system and 3) the role of norepinephrine in the pathogenesis of ventricular hypertrophy. With the capability of long-term intravenous infusion of substances in the dog, a method is availble for studying the influence of humoral substances in the hypertrophy process anf for testing chemical substances which may be efficacious in therapy of heart failure. One of our major goals has been to discover the structural and ultrastructural basis for acute and chronic overload to the heart; emphasis will be placed on 1) the intercalated disc - (multiple, widened and separated intercalated discs) 2) ribosomes, 3) the mitochondria, and 4) the sarcoplasmic reticulum. A special study will be made of the calcium sarcoplasmic reticulum system in the normal and overloaded ventricle. Human myocardial biopsies will be obtained from patients with systolic and diastolic ventricular overloads to relate structure with function. An additional study of the myosin subunits and purified myosin ATPase changes has been undertaken in the overloaded ventricle.